Two complementary approaches will be utilized to study the interactions that occur between neurons and glial cells in both normal and pathological states. First, in vitro studies will be undertaken on 99% pure primary cultures of neurons and glia from both sympathetic ganglia and cerebral cortical tissue. These isolated cultures will be prepared by a new method of cell fractionation based on differential cell adhesiveness. These cultures will be further characterized biochemically and histologically. A marked stimulation of non-neuron cell proliferation by neurons ("gliosis") has already been observed in such cultures. Possible mechanisms for this interaction will be examined in detail. Evidence for other neuronal glial interactions will be sought and a specific hypothesis concerning regulation of glial metabolism during neuronal activity will be tested. Second, in vivo studies will be carried out on glial cells in four experimental settings in which changes in the ration of glia to neurons have been induced or occur naturally (e.g., (1) developing mice and rats, (2) Frings mice susceptible to audiogenic seizures, (3) experimentally elicited epileptogenic and mirror foci, ad (4) mice subjected to chronic electroshock). In each of these model systems, biochemical parameters specific for glial cells will be studied in relation to neuronal function in the presence and absence of drugs selective for these cell types. Also the mechanism of seizure induction by perchlorate and thiocyanate will be examined in order to test our hypothesis that these agents may produce convulsions by inhibition of anion transport systems in the glial cells. The suitability of such seizures as a model for epilepsy will be studied. Correlated in vitro studies will be undertaken on the mechanism of perchlorate-induced seizures and on the nature of neuronal-glial interactions in the brains of Frings mice.